1. Field of the Invention
This invention is directed to methods for treating aneurysms in a mammalian patient.
The following publications are cited in this application as superscript numbers:
1 Castaneda-Zuniga, et al., Interventional Radiology, in Vascular Embolotherapy, Part 1, 1:9-32, Williams and Wilkins, Publishers (1992)
2 Greff, et al., Compositions for Use in Embolizing Blood Vessels, U.S. Pat. No. 5,667,767, issued Sep. 16, 1997
3 Evans, et al., Cellulose Diacetate Compositions for Use in Embolizing Blood Vessels, U.S. Pat. No. 5,580,568, issued Dec. 3, 1996
4 Evans, et al., Novel Embolizing Compositions, U.S. Pat. No. 5,695,480, issued Dec. 9, 1997
5 Jones, et al., Methods for Embolizing Vascular Sites with an Embolizing Composition Comprising Dimethylsulfoxide, U.S. Pat. No. 5,830,178, issued Nov. 3, 1998
6 Whalen, et al., Novel Embolizing Compositions Comprising High Polymer Concentrations, U.S. patent application Ser. No. 09/574,379, filed May 19, 2000
7 Evans, et al., Methods for Embolizing Blood Vessels, U.S. Pat. No. 5,702,361, issued Dec. 30, 1997
8 Evans, et al., Methods for Embolizing Blood Vessels, U.S. Pat. No. 6,017,977, issued Jan. 25, 2000
9 Wallace, et al., Intracranial Stent and Method of Use, U.S. Pat. No. 6,007,573, issued Dec. 28, 1999.
10 Racchini, et al., Porous Balloon For Selective Dilation and Drug Delivery, U.S. Pat. No. 5,458,568, issued Oct. 17, 1995
11 Whalen, et al., Novel High Viscosity Embolizing Compositions, U.S. patent application Ser. No. 09/574,379, May 19, 2000
12 Szikora, et al., Endovascular Treatment of Experimental Aneurysms with Liquid Polymers: The Protective Potential of Stents, Neurosurgery, 38(2):339-347 (1996)
13 Kinugasa, et al., Direct Thrombosis of Aneurysms with Cellulose Acetate Polymer, Part IIxe2x80x94Preliminary Clinical Experience, J. Neurosurg., 77:501-507 (1992)
14 Kinugasa, et al., Cellulose Acetate Polymer Thrombosis for the emergency Treatment of Aneurysms: Angiographic Finding, Clinical Experience, and Histopathological Study, Neurosurgery, 34:694-701 (1994)
15 Mandai, et al., Direct Thrombosis of Aneurysms with Cellulose Acetate Polymer: Part Ixe2x80x94Results of Thrombosis in Experimental Aneurysms, J. Neurosurg., 77:497-500 (1992)
16 Talia, et al., Bioabsorbable and Biodegradable Stents in Urology, J. Endourology, 11(6):391 (1997)
17 Wallace, et al., Intracranial Stent, U.S. Pat. No. 6,254,628, issued Jul. 3, 2001.
18 Dunn, et al., U.S. Pat. No. 4,938,763 for xe2x80x9cBiodegradable In-Situ Forming Implants and Methods for Producing Samexe2x80x9d issued Jul. 3, 1990.
19 xe2x80x9cCANCER, Principles and Practice of Oncologyxe2x80x9d, 4th Ed., Volume 1, xe2x80x9cCancer Treatmentxe2x80x9d, pp. 545-548 (1993).
All of the above references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated herein by reference in its entirety.
2. State of the Art
Aneurysms arise in mammalian subjects and, in particular, human subjects as a result of vascular disease wherein the arterial (wall) weakens and, under pressure due to blood flow, the arterial wall xe2x80x9cballoonsxe2x80x9d. Continued growth and/or eventual rupture of the ballooned arterial wall is associated with high morbidity and mortality rates. Intracranial aneurysms are of particular concern because surgical procedures to treat these aneurysms before rupture are often not feasible and further because rupture of these aneurysms can have devastating results on the patient even if the patient survives rupture. Accordingly, treatment protocols for intracranial aneurysms may be prophylactic in nature, i.e., to inhibit rupture or rerupture of the aneurysm rather than to inhibit bleeding from the ruptured aneurysm.
Methods well documented in the art to inhibit intracranial aneurysmal rupture include the delivery into the aneurysmal sac of non-particulate agents such as metal coils which are designed to induce thrombosis after delivery to the aneurysm thereby inhibiting blood flow into the aneurysm1; delivery of a fluid composition into the aneurysmal sac which composition solidifies in the sac to inhibit blood flow into the aneurysm2-6; or a delivery of a combination of non-particulate agents and a fluidic composition into the aneursymal sac to inhibit blood flow into the aneurysm.7-8 
In each case, the cranial aneurysm is treated by filling the aneurysmal sac in a manner which inhibits blood flow into the sac. This reduced blood flow correlates to reductions in aneurysmal pressure and, hence, a reduction in the likelihood of rupture. However, care must be taken to ensure against migration of non-particulate agents or fluid composition beyond the aneurysmal sac (which can occur, for example, by overfilling of the sac) because this can result in parent artery or distal embolization which, in turn, has its own high level of morbidity associated therewith.12 
Notwithstanding the benefits that these methods provide in inhibiting aneurysmal rupture, in a significant number of cases, the treatment protocol is only effective for a short period of time due to reformation of the aneurysmal sac or formation of a new aneurysmal sac at or adjacent the previously treated aneurysm in the treated patient.13-15 
Upon careful analysis, this invention is based upon the discovery that subsequent re-treatment arising after initial treatment of the aneurysm by filling the aneurysmal sac with non-particulate agents and/or fluidic compositions was necessitated because the initial treatment did not address all of the diseased tissue. Specifically, the aneurysmal sac in the parent artery often reflects only the most diseased and hence weakest portion of the arterial wall. However, regions proximal and distal to the aneurysmal sac are often diseased and prone to ballooning. Hence, when the aneurysmal sac is filled via the methods described above, other diseased portions of the arterial wall adjacent to the treated aneurysm become more likely to balloon and rupture. It is this latter phenomena that is believed to result in retreatment of the aneurysm.
While Szikora, et al.12 discloses the use of a porous stent in combination with a fluid composition in treating an aneurysm, the stent employed is a porous stent and the amount of polymer employed is less than that necessary to completely fill the aneurysmal sac. Accordingly, the techniques disclosed therein do not isolate the parent artery proximal and distal to the aneurysmal sac from blood flow.
This invention is directed to methods for treating aneurysms wherein the aneurysmal sac is filled with a non-particulate agent or plurality of such agents and/or with a fluid composition which solidifies in situ. Filling of the aneurysmal sac employs sufficient amount of the non-particulate agent or plurality of such agents and/or the fluid composition to inhibit blood flow into the aneurysm sac. In addition, the methods of this invention also provide for non-endogenous isolation of the parent artery proximal and distal to the aneurysmal sac from systemic blood flow of the treated mammal. The combination of these features provides for treatment of the aneurysmal sac while, at the same time, inhibiting aneurysm formation and/or regrowth in the diseased portions of the arterial wall proximal and distal to the treated aneurysm.
Preferably, the aneurysm treated is an intracranial (cerebral) aneurysm.
Accordingly, in one of its method aspects, this invention is directed to a method for treating an aneurysm in a mammalian patient which method comprises:
(a) identifying the vascular site of an aneurysm in a mammalian patient wherein said aneurysm comprises an aneursymal sac formed from the vascular wall of a parent artery and further wherein said aneurysmal sac participates in the systemic blood flow of said patient;
(b) inhibiting systemic blood flow into said aneurysmal sac by filling at least a portion of said sac with a fluid composition and/or a non-particulate agent or plurality of said agents; and
(c) non-endogenously isolating the parent artery proximal and distal to said aneurysm from systemic blood flow.
In the methods described above, the non-particulate agents preferably comprise metallic coils and, more preferably, platinum coils.
The fluid composition employed in the methods of this invention preferably comprises either a biocompatible polymer or a biocompatible prepolymer. When a biocompatible polymer is employed, the fluid composition preferably comprises a biocompatible polymer, a biocompatible contrast agent, and a biocompatible solvent which solubilizes the biocompatible polymer wherein sufficient amounts of the polymer are employed in the composition such that, upon delivery to the aneurysm, a polymer precipitate forms which fills at least a portion of the aneurysmal sac thereby inhibiting blood flow therein. Preferably, the viscosity of the polymer composition is at least about 150 cSt at 40xc2x0 C.
Such polymer composition can comprise, for example, a biocompatible polymer at a concentration of from about 2 to 50 weight percent; a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent; and a biocompatible solvent from about 10 to 88 weight percent wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition.
Preferably, in this particular composition, the concentration of the polymer ranges from 6 to 50 weight percent and more preferably 8 to 30 weight percent.
Preferably, the polymer composition has a viscosity of at least about 150, preferably at least about 200 and more preferably at least 500 cSt at 40xc2x0 C. More preferably the viscosity ranges from about 200 to 40,000 cSt at 40xc2x0 C., more preferably from about 500 to 40,000 cSt at 40xc2x0 C. In another embodiment, the viscosity ranges from about 500 to 5000 cSt at 40xc2x0 C.
In another aspect of this invention, the biocompatible polymer can be replaced with a biocompatible prepolymer and, when so used, the presence of the biocompatible solvent becomes optional.
In a further preferred embodiment, the biocompatible solvent is dimethylsulfoxide (DMSO), ethanol, ethyl lactate or acetone.
Isolation of the parent artery proximal and distal to said aneurysm from systemic blood flow is preferably accomplished by placement of a stent adjacent the aneurysmal sac which stent extends in both the proximal and distal directions of the parent artery beyond the aneurysmal sac and isolates blood flow to the arterial walls of the parent artery overlayed by the stent. The stent employed can be either formed in situ or placed in the artery by microcatheter techniques.
Alternatively, the use of novel balloon catheters allow for the use of fluid compositions to form a coherent precipitate in the aneurysmal sac and which extends from the neck of the sac both distally and proximally to both fill the aneurysmal sac and to isolate the parent artery from the systemic blood flow both distally and proximally from the site of the aneurysm.
In either case, the methods of this invention entail the non-endogenous isolation of the parent artery wall to the systemic blood flow both proximal and distal to the site of the aneurysmal sac. The parent artery is isolated either immediately adjacent the aneurysmal sac or around the entire inner circumference of the parent artery. The parent artery is preferably isolated by at least about 2 to 10 mm proximal and distal to said aneurysm from systemic blood flow and more preferably by no more than about 3 to 5 mm proximal and distal to said aneurysm.